Audible indicator

ABSTRACT

The disclosure relates to an audible indicator for use with a drug delivery device comprising a bistable resilient force member capable of residing in two states. In a biased state, the resilient force member is biased and stores energy In a relaxed state, the resilient force member is relaxed. The resilient force member releases the stored energy when transitioning from the biased state into the relaxed state, thereby generating an audible signal.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is the national stage entry of InternationalPatent Application No. PCT/EP2016/062450, filed on Jun. 2, 2016, andclaims priority to Application No. EP 15170584.5, filed in on Jun. 3,2015, the disclosures of which are expressly incorporated herein inentirety by reference thereto.

TECHNICAL FIELD

The disclosure relates to an audible indicator.

BACKGROUND

Administering an injection is a process that presents a number of mentaland physical risks and challenges for users and healthcareprofessionals. Injection devices typically fall into two categoriesmanual devices and autoinjectors. In a conventional manual device,manual force is required to drive a medicament through a needle. This istypically done by some form of button/plunger that has to becontinuously pressed during the injection. There are numerousdisadvantages associated with this approach. For example, if thebutton/plunger is released prematurely, the injection will stop and maynot deliver an intended dose. Furthermore, the force required to pushthe button/plunger may be too high (e.g., if the user is elderly or achild). Additionally, aligning the injection device, administering theinjection, and keeping the injection device still during the injectionmay require dexterity which some patients (e.g., elderly patients,children, arthritic patients, etc.) may not have.

Autoinjector devices aim to make self-injection easier for patients. Aconventional autoinjector may provide the force for administering theinjection by a spring and a trigger button or other mechanisms used toactivate the injection. Autoinjectors may be single-use or reusabledevices.

Furthermore, it is necessary to administer the full dose in order toachieve full effectiveness of the medicament within the patient.

SUMMARY

According to aspects of the current disclosure, there is provided anaudible indicator for use with a drug delivery device, the audibleindicator comprising a bistable resilient force member configured toreside in either of two states, having two different conformations. In arelaxed state, the resilient force member is relaxed in a firstconformation. In a biased state, the resilient force member is biased tostore energy in a second conformation different to the firstconformation. The resilient force member releases stored energy togenerate an audible signal when changing from the biased state into therelaxed state due to a transition from the second conformation to thefirst conformation.

The resilient force member may be configured as a bistable springelement. A bistable spring element has two stable states orconformations in which it can rest without support from an externalcomponent. In order to move the bistable spring element from one stablestate or conformation to the other, energy has to be used to move thebistable spring element into an intermediate state. This energy is thenreleased as the bistable spring moves out of the intermediate state intoone of the stable states.

The audible indicator can be used for indicating to a patient or userthat the full dose of medicament in the drug delivery device was spent.Thus, the drug delivery device is improved in order to achieve areliable indication of the end of medicament delivery and a fulleffectiveness of the medicament within the patient.

The resilient force member may change from the biased state into therelaxed state by a movement of a plunger, used to displace the drug froma medicament container. For example, the resilient force member maychange from the biased state into the relaxed state when the plungermoves towards or reaches a proximal position at the end of a medicamentdelivery process.

In an exemplary embodiment, the resilient force member includes a leafspring having a longitudinal axis, wherein the resilient force member isbent by a certain angle about the longitudinal axis forming two angledwing-shaped sections. This enables a priming of the audible indicatorwith little effort.

In an exemplary embodiment, the leaf spring has a rectangular shape, asquare shape or an oval shape

The resilient force member is configured as a bistable spring element.The resilient force member may be supported in the biased state in orderto prevent transition into the relaxed state.

It is understood that a bistable leaf spring can store energy in theform of tension on one or more outer edges of one or more wing-shapedsections. It is also understood that the bistable leaf spring can alsostore energy in the form of compression in a central region of one ormore wing-shaped sections.

For example, the resilient force member is supported when the drugdelivery device is in an initial state and the resilient force member isunsupported when the drug delivery device is in a primed state.Alternatively, the resilient force member is supported when the drugdelivery device is in an initial state and in a primed state, wherein aproximal spring section of the resilient force member is supported by asupporting protrusion arranged on a rear case, or in that the resilientforce member is unsupported in the biased state. The resilient forcemember may thus change from the biased state into the relaxed state whena proximal plunger section abuts a distal spring section, wherein thedistal spring section is bent about an axis that is perpendicular to thelongitudinal axis with respect to an intermediate spring section or withrespect to a proximal spring section when the resilient force member isin the biased state.

For example, the audible indicator comprises a projection, e.g. ahook-like projection, that is arranged on the distal spring section andsupported by a supporting rib arranged on a needle shroud. Theengagement between the hook-like projection and the supporting ribprevents a premature activation of the resilient force member duringstorage and transportation.

Alternatively, there may be provided a collar that is coupled to theplunger and adapted to support the distal spring section. The engagementbetween the distal spring section and the collar prevents a prematureactivation of the resilient force member during storage andtransportation.

In an alternative embodiment, the resilient force member is supportedwhen the drug delivery device is in an initial state and in a primedstate, wherein a proximal spring section of the resilient force memberis supported by a supporting protrusion arranged on a rear case. Thus,the resilient force member may change from the biased state into therelaxed state when an activating rib of a needle shroud abuts a proximalspring section, wherein the proximal spring section is bent about anaxis that is perpendicular to the longitudinal axis with respect to adistal spring section when the resilient force member is in the biasedstate.

According to a further alternative embodiment, the resilient forcemember is unsupported in the biased state. For example, the resilientforce member comprises a proximal spring section and a distal springsection, wherein the distal spring section is bent about an axis that isperpendicular to the longitudinal axis with respect to the proximalspring section when the resilient force member is in the biased state.Thus, the resilient force member may transition from the biased stateinto the relaxed state when a proximal plunger section abuts the distalspring section. Alternatively, the resilient force member comprises akink tip, wherein the resilient force member may transition from thebiased state into the relaxed state when a proximal plunger sectionabuts the kink tip.

In an exemplary embodiment the audible indicator may be adapted toindicate completion of medicament delivery, wherein the resilient forcemember includes a leaf spring comprising on or more wing-shaped sectionsadapted to store energy on one or more outer edges or in a centralregion of the one or more wing-shaped sections, and wherein theresilient force member changes from the biased state into the relaxedstate, when the one or more wing-shaped sections pivot about a certainangle until the resilient force member reaches the first conformation.

The audible indicator may be part of a drug delivery device.

In some embodiments, a method of assembling a drug delivery device cancomprise the steps of bending a resilient force member about alongitudinal axis extending generally from a first end of the resilientforce member to a second end of the resilient force member locatedgenerally opposite the first end. For example, the first end may be adistal end and the second send may be a proximal end of the resilientforce member. In some embodiments, the resilient force member can bebent about the longitudinal axis or bend such that the two-wing-shapedsections are at an angle of between about 130 degrees and about 160degrees relative to each other. For example, the angle can be between130 degrees and 140 degrees or between 140 degrees and 155 degrees orbetween 132 degrees and 142 degrees or between 134 degrees and 140degrees or between 136 degrees and 138 degrees. In an exemplaryembodiment, the angle is approximately or exactly 136 degrees or 137degrees or 138 degrees or 148 degrees or 152 degrees.

Such bending may plastically deform the resilient force member to formtwo wing-shaped sections angled relative to each other about thelongitudinal axis. The two sections may have approximately the sameshape or size. With such bending, the resilient force member may assumea first conformation.

The assembly method can also include flexing the resilient force memberabout an axis (A) running substantially perpendicular to thelongitudinal axis or bend described above. Such flexing may elasticallydeform the resilient force member, converting its state from a relaxedstate (S1) to a biased state (S2). In the biased state, the resilientforce member can assume a second conformation different to the firstconformation.

As described herein, the biased state can be unsupported (e.g.,bistable), where no additional forces are applied to the resilient forcemember to maintain the second conformation. The biased state can also bemaintained with support (e.g., monostable), where one or more additionalor retaining forces are applied to the resilient force member tomaintain the second conformation. Converting a bistable member from S2to S1 can require application of an additional force to the resilientforce member, while converting a monostable member from S2 to S1 canrequire at least partial removal of a retaining force from the resilientforce member. Conversion from S2 to S1 can cause the resilient forcemember to generate a surprisingly loud sound signal.

The method can further include coupling the resilient force member ofthe drug delivery device. For example, the resilient force member can befixedly coupled or movingly coupled to one or more parts of the drugdelivery device. Fixed coupling can include co-molding, adhesive orchemical bonding, screws, etc. Moveable coupling can include locating atleast part of the resilient force member within a complementary recess,or providing the resilient force member with one or more complementaryrecesses. For example, the resilient force member can include one ormore protrusions designed to fit generally within one or morecomplementary recesses of a syringe carrier. The one or more protrusionscan be located at various positions on the resilient force member. Theresilient force member can also include one or more complementaryrecesses or a combination of protrusion or recess. Such an arrangementof one or more protrusions and recesses can facilitate efficientcomponent transport, priming of the resilient force member, componentassembly, or assembly of the device.

Further scope of applicability of the present invention will becomeapparent from the detailed description given hereinafter. However, itshould be understood that the detailed description and specificexamples, while indicating exemplary embodiments of the invention, aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

The accompanying drawings are given by way of illustration only, andthus, are not limitative of the present invention.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a schematic perspective partial section of a drug deliverydevice comprising an audible indicator according to a first embodiment,

FIG. 2 is a schematic perspective view of the audible indicatoraccording to the first embodiment in a pre-assembled state,

FIG. 3 is a schematic perspective view of the audible indicatoraccording to the first embodiment in a primed state,

FIG. 4 is a schematic longitudinal section of a drive sub assembly ofthe drug delivery device comprising a rear case, a plunger and theaudible indicator according to the first embodiment in the primed state,

FIG. 5 is a diagram with a force-bending curve of the audible indicatoraccording to the first embodiment,

FIG. 6 is a schematic longitudinal section of the drive sub assemblywith the audible indicator according to FIG. 4 in a relaxed state,

FIG. 7 is a schematic perspective partial section of a drug deliverydevice comprising an audible indicator according to a second embodiment,

FIG. 8 is a schematic perspective view of the audible indicatoraccording to the second embodiment,

FIG. 9 is a schematic perspective view of a drive sub assembly of thedrug delivery device comprising a rear case, a plunger and the audibleindicator according to the second embodiment,

FIG. 10 is a schematic longitudinal section of a proximal part of a drugdelivery device in a primed state comprising the audible indicatoraccording to the second embodiment,

FIG. 11 is a schematic longitudinal section of the proximal part of thedrug delivery device with the audible indicator according to FIG. 10 ina relaxed state,

FIG. 12 is a schematic perspective partial section of a drug deliverydevice comprising an audible indicator according to a third embodiment,

FIG. 13 is a schematic perspective view of the audible indicatoraccording to the third embodiment in a pre-assembled state,

FIG. 14 is a schematic perspective view of a drive sub assembly of thedrug delivery device comprising a rear case, a plunger and the audibleindicator according to the third embodiment,

FIG. 15 is a schematic longitudinal section of the drive subassemblycomprising the audible indicator according to the third embodiment in aprimed state,

FIG. 16 is a schematic longitudinal section of the drive sub assemblyaccording to FIG. 15 comprising the audible indicator according to thethird embodiment in a relaxed state,

FIG. 17 is a schematic perspective partial section of a drug deliverydevice comprising an audible indicator according to a fourth embodiment,

FIG. 18 is a schematic perspective view of the audible indicatoraccording to the fourth embodiment in a pre-assembled state,

FIG. 19 is a schematic perspective view of a drive sub assembly of thedrug delivery device comprising a rear case, a plunger and the audibleindicator according to the fourth embodiment,

FIG. 20 is a schematic longitudinal section of a proximal part of a drugdelivery device in an initial state comprising the audible indicatoraccording to the fourth embodiment in a biased state,

FIG. 21 is a schematic longitudinal section of the proximal part of thedrug delivery device in a primed state with the audible indicatoraccording to FIG. 20 in the biased state,

FIG. 22 is a schematic longitudinal section of the proximal part of thedrug delivery device with the audible indicator according to FIG. 20 ina relaxed state,

FIG. 23 is a schematic perspective partial section of a drug deliverydevice comprising an audible indicator according to a fifth embodiment,

FIG. 24 is a schematic perspective view of the audible indicatoraccording to the fifth embodiment in a pre-assembled state,

FIG. 25 is a schematic perspective view of a collar,

FIG. 26 is a schematic perspective view of a drive sub assembly of thedrug delivery device comprising a rear case, a plunger, the collaraccording to FIG. 25 and the audible indicator according to the fifthembodiment,

FIG. 27 is a schematic longitudinal section of a proximal part of a drugdelivery device in an initial state comprising the audible indicatoraccording to the fifth embodiment in a biased state,

FIG. 28 is a schematic longitudinal section of a cut out of the drugdelivery device according to FIG. 23 with the collar according to FIG.25,

FIG. 29 is a schematic longitudinal section of the proximal part of thedrug delivery device in a primed state with the audible indicatoraccording to FIG. 27,

FIG. 30 is a schematic longitudinal section of the proximal part of thedrug delivery device with the audible indicator according to FIG. 27 ina relaxed state,

FIG. 31 is a schematic perspective partial section of a drug deliverydevice comprising an audible indicator according to a sixth embodiment,

FIG. 32 is a schematic perspective view of the audible indicatoraccording to the sixth embodiment in a pre-assembled state,

FIG. 33 is a schematic perspective view of a drive sub assembly of thedrug delivery device comprising a rear case, a plunger and the audibleindicator according to the sixth embodiment,

FIG. 34 is a schematic longitudinal section of a proximal part of a drugdelivery device in a primed state comprising the audible indicatoraccording to the sixth embodiment in a biased state,

FIG. 35 is a schematic longitudinal section of the proximal part of thedrug delivery device with the audible indicator according to FIG. 34 ina relaxed state,

FIG. 36 is a schematic perspective partial section of a drug deliverydevice comprising an audible indicator according to a seventhembodiment,

FIG. 37 is a schematic perspective view of the audible indicatoraccording to the seventh embodiment in a pre-assembled state,

FIG. 38 is a schematic perspective view of a drive sub assembly of thedrug delivery device comprising a rear case, a plunger and the audibleindicator according to the seventh embodiment,

FIG. 39 is a schematic longitudinal section of a proximal part of a drugdelivery device in a primed state comprising the audible indicatoraccording to the seventh embodiment in a biased state,

FIG. 40 is a schematic longitudinal section of the proximal part of thedrug delivery device with the audible indicator according to the seventhembodiment in a relaxed state.

Corresponding parts are marked with the same reference symbols in allFigures.

DETAILED DESCRIPTION

In the present application, when the term “distal section/end” is used.This refers to the section/end of the device, or the sections/ends ofthe components thereof, which during use of the device is locatedclosest to a medicament delivery site of a patient. Correspondingly,when the term “proximal section/end” is used, this refers to thesection/end of the device, or the sections/ends of the componentsthereof, which during use of the device is pointing away from themedicament delivery site of the patient.

FIGS. 1 to 6 respectively show a first embodiment of an audibleindicator 13 of an exemplary embodiment of a drug delivery device 1which will be described further below.

FIG. 1 is a schematic perspective partial section of an exemplaryembodiment of the drug delivery device 1 configured as an autoinjector.

In the shown exemplary embodiment, the drug delivery device 1 comprisesa case 2 with a front case 2.1 and a rear case 2.2. The case 2 isadapted to hold a medicament container 3, such as a syringe. (Themedicament container is referred to hereinafter as the “syringe 3”). Thesyringe 3 may be a pre-filled syringe, in particular a 1.0 ml pre-filledsyringe, containing a medicament M and having a needle 4 arranged at adistal end of the syringe 3. In another exemplary embodiment, themedicament container 3 may be a cartridge which includes the medicamentM and engages a removable needle (e.g., by threads, snaps, friction,etc.).

The drug delivery device 1 further comprises a protective needle sheath5 that is coupled to the needle 4. For example, the protective needlesheath 5 is removably coupled to the needle 4. The protective needlesheath 5 may be a rubber needle sheath or a rigid needle sheath which iscomposed of rubber and a full or partial plastic shell.

For sealing the syringe 3 proximally and for displacing a medicament Mcontained in the syringe 3 through the needle 4, a stopper 6 is providedand arranged within the syringe 3.

In the shown exemplary embodiment, the drug delivery device 1 comprisesa needle shroud 7 that is telescopically coupled to the case 2 andmovable between a first extended position relative to the case 2 inwhich the needle 4 is covered and a retracted position relative to thecase 2 in which the needle 4 is exposed. Furthermore, a shroud spring 8is arranged to bias the needle shroud 7 distally against the case 2.

Furthermore, a drive spring 9 is arranged within the case 2.Furthermore, a plunger 10 serves for forwarding a force of the drivespring 9 to the stopper 6. The plunger 10 may be hollow, wherein thedrive spring 9 is arranged within the plunger 10, biasing the plunger 10distally against the case 2. In another exemplary embodiment, theplunger 10 may be solid and the drive 9 may engage a proximal end of theplunger 10. In the shown exemplary embodiment, the drive spring 9 iswrapped around an outer diameter of the plunger 10 and extends withinthe syringe 3. The plunger 10 may comprise a proximal plunger section10.1 and a distal plunger section 10.2 that are configured withdifferent diameters, wherein the diameter of the proximal plungersection 10.1 is larger than the diameter of the distal plunger section10.2 (not shown in detail in FIGS. 1, 4 and 6).

Additionally, the drug delivery device 1 comprises a cap 11 that may beremovably disposed at a distal end of the case 2, in particular at adistal end of the front case 2.1. The cap 11 may comprise grip features11.1 for facilitating a removal of the cap 11, e.g., by twisting and/orpulling the cap 11 off the case 2. The cap 11 may further include a gripelement 11.2, e.g., a barb, a hook, a narrowed section, etc., arrangedto engage the protective needle sheath 5, the case 2 and/or the needleshroud 7.

In the shown exemplary embodiment, a plunger release mechanism 12 isarranged for preventing release of the plunger 10 prior to retraction ofthe needle shroud 7 relative to the case 2 and for releasing the plunger10 once the needle shroud 7 is sufficiently retracted.

Furthermore, a shroud lock mechanism 14 is arranged to preventretraction of the needle shroud 7 relative to the case 2 when the cap 11is in place, thereby avoiding unintentional activation of the drugdelivery device 1, e.g., if dropped, during shipping or packaging, etc.The shroud lock mechanism 14 may comprise one or more compliant beams11.3 on the cap 11 and a respective number of apertures 7.6 in theneedle shroud 7 adapted to receive each of the compliant beams 11.3.

When the cap 11 is attached to the drug delivery device 1, the compliantbeams 11.3 abut a radial stop 2.15 on the case 2, which prevents thecompliant beams 11.3 from disengaging the apertures 7.6. Furthermore,when the cap 11 is attached to the drug delivery device 1, an axialproximal movement of the cap 11, relative to the case 2, is limited by arib 11.4 on the cap 11 that abuts the case 2.

When the cap 11 is pulled off the case 2 distally, the compliant beams11.3 may abut an edge of the aperture 7.6 and deflect to disengage theaperture 7.6, allowing for removal of the cap 11 and the protectiveneedle sheath 5 attached thereto. In an exemplary embodiment, thecompliant beams 11.3 and/or the apertures 7.6 may be ramped to reduceforce necessary to disengage the compliant beams 11.3 from the apertures7.6.

The drug delivery device 1 further comprises the audible indicator 13according to the first embodiment for producing an audible feedback fora user or patient indicating completion of medicament delivery. In otherwords: The audible indicator 13 is provided to indicate to a user or apatient that the full dose of medicament M was spent.

In the following FIGS. 2 to 6, the audible indicator 13 according to thefirst embodiment will be explained in more detail.

FIGS. 2 and 3 are schematic perspective views of the audible indicator13 according to the first embodiment, wherein FIG. 2 shows the audibleindicator 13 in a pre-assembly state and FIG. 3 in a primed state.

The audible indicator 13 comprises a resilient force member 13.1, e.g.having a substantially rectangular shape, comprising a longitudinal axisL running in parallel to the longest side of the outer circumference ofthe resilient force member 13.1. In other embodiments, the resilientforce member 13.1 may have a triangular shape or any other geometricalshape suitable to couple the audible indicator 13 to the autoinj ector1.

The resilient force member 13.1 may be designed as a monostable leafspring comprising a resilient material, e. g. spring steel or springplastic. Thus, the resilient force member 13.1 is capable of residing intwo states. That is, the resilient force member 13.1 may assume twodifferent conformations, one of them stable with limited or noapplication of an external force and the other one unstable. Forexample, these two states can include a first or relaxed state S1 (orpre-assembly state, or triggered state), in which the resilient forcemember 13.1 has a first conformation. In a second or biased state S2 (orprimed state), the resilient force member 13.1 can have a secondconformation. In FIG. 2, the resilient force member 13.1 is in therelaxed state S1, which can correspond to the pre-assembly state as wellas to a state at the end of medicament delivery.

Regarding the first embodiment, the resilient force member 13.1comprises a longitudinal bend 13.2. The longitudinal bend 13.2 can bearranged generally in the centre of the resilient force member 13.1running in parallel to the longitudinal axis L. The longitudinal bend13.2 can divide the audible indicator 13 into two wing-shaped sectionsangled to each other with an angle less than 180 degrees. In theillustrated perspective of FIG. 2, the wing-shaped sections are angleddownwards.

Furthermore, the resilient force member 13.1 can comprise one or moretabs 13.3 projecting radially from the outer circumference.Specifically, the resilient force member 13.1 can include one, two,three four or more tabs 13.3. As shown in FIGS. 2 and 3, the resilientforce member 13.1 includes four tabs 13.3, wherein one pair of tabs 13.3is arranged opposite another pair of tabs 13.3. In another embodiment(not shown), the resilient force member 13.1 can include two tabs 13.3located generally opposite each other. The pairs of tabs 13.3 arearranged spaced to each other in the direction of the longitudinal axisL. In another exemplary embodiment, the number and arrangement of thetabs 13.3 may differ from the shown exemplary embodiment. In anexemplary embodiment, the tabs 13.3 may be angled with respect to thewing-shaped sections to facilitate assembly of the drug delivery device1.

The audible indicator 13 is coupled to the case 2 as shown in FIG. 1. Indetail, the resilient force member 13.1 is held in the rear case 2.2such that the longitudinal axis L is in parallel with a longitudinalextension of the drug delivery device 1. The audible indicator 13 iscoupled to the drug delivery device 1 by a snap connection, wherein oneor more of the tabs 13.3 are engaged within a number of correspondingopenings (not shown) in the rear case 2.2. In another exemplaryembodiment, the resilient force member 13.1 is held in the rear case 2.2by a frictional connection, such as a screw or rivet connection orinterference fit.

For assembling the audible indicator 13 into the drug delivery device 1,the resilient force member 13.1 is bent in the centre about an axis Arunning perpendicular to the longitudinal axis L. The bending angle isless than 90 degrees. This bending is achieved by applying apredetermined force onto or near the centre point of the resilient forcemember 13.1 when engaging the tabs 13.3 within the openings in the rearcase 2.2. As a result, the resilient force member 13.1 changes from therelaxed state S1 into the biased state S2. Two ends 13.1.1, 13.1.2 ofthe resilient force member 13.1 at opposite ends along the longitudinalaxis L are angled upwards from the centre point in the illustratedperspective of FIG. 3, which shows the biased state S2. Hence, thebiased state S2 corresponds with the primed state, wherein the resilientforce member 13.1 stores a certain amount of energy.

After removing the applied force, the resilient force member 13.1 isheld in the biased state S2 as it is shown in FIG. 4 and describedbelow.

FIG. 4 shows a longitudinal section of an exemplary embodiment of adrive subassembly 1.1 of the drug delivery device 1.

The drive sub assembly 1.1 is a sub assembly of the drug delivery device1 and comprises the components required to deliver the medicament M. Thedrive subassembly 1.1 comprises the rear case 2.2, the plunger 10 andthe audible indicator 13 according to the first embodiment. The drugdelivery device 1 further comprises a front sub assembly (not shownseparately) to allow for flexibility as to the time and location ofmanufacture of the subassemblies and final assembly with the syringe 3.

According to the present embodiment, the rear case 2.2 comprises twosupport arms 15.1 adapted to support an axial position of the syringe 3during storage, transportation and medicament delivery. The support arms15.1 project distally from a distal end of the rear case 2.2. The rearcase 2.2 further comprises an additional flexible arm 15.2 that projectsdistally from the distal end of the rear case 2.2 as well. The flexiblearm 15.2 is adapted to damp impact forces and thus to stabilize theresilient force member 13.1 in its biased state S2 during storage,transportation, and medicament delivery.

The resilient force member 13.1 is in the biased state S2 and held inthe rear case 2.2 by the snap connection as described above. Thedistally pointing end 13.1.1 of the resilient force member 13.1 issupported by a projection 15.2.1 of the flexible arm 15.2 arranged on adistal end of the flexible arm 15.2. The proximally pointing end 13.1.2of the resilient force member 13.1 is free and not in contact with anyother component and is located above the flexible arm 15.2, or anothersection of the rear case 2.2. In an exemplary embodiment, the rear case2.2 may comprise a plurality of flexible arms 15.2 that are arrangedaround a circumference of the proximal end of the rear case 2.2.

Furthermore, the flexible arm 15.2 is deflected outwards supported bythe outer circumference of the plunger 10 as is shown in FIG. 4.

After changing from the relaxed state S1 into the biased state S2 asdescribed before, only a small force may be required to hold theresilient force member 13.1 in the biased state S2. This is achieved bythe longitudinal bend 13.2 that provides a bended cross section of theresilient force member 13.1 which, buckles into a new configuration bychanging from the relaxed state S1 into the biased state S2. In thisconfiguration, a stiffness of the material structure is significantlyreduced and thus only a small holding force is required to maintain theresilient force member 13.1 in the biased state S2. FIG. 5 shows adiagram with a force-bending curve C of the resilient force member 13.1.

The diagram comprises an abscissa x and an ordinate y. The abscissa xrepresents the bending deflection and the ordinate y represents theforce required for achieving this deflection. The maximum of the forceis represented by the coordinates x2, y1. Until this maximum is reachedstarting from the relaxed state S1 at zero deflection and force, removalof the force results in the resilient force member 13.1 returning intothe relaxed state S1. The maximum at the coordinates x2, y1 represent anequilibrium point for the resilient force member 13.1 to change from therelaxed state S1 into the biased state S2, i.e. the deflection increasesfurther without an additional increase in force such that the curvearrives at the coordinates x1, y2. At this point, a much lower forcethan the at the maximum (y2) is sufficient to hold the resilient forcemember 13.1 in the biased state S2. Thus, a large amount of energy canbe stored by the resilient force member 13.1 in the biased state S2whilst maintaining a low holding force.

The low holding force in the biased state S2 may cause a smallfrictional drag on the plunger 10, diverting a small amount of theenergy of the drive spring 9 away during medicament delivery, whereinthe plunger 10 is moved distally by a release of the energy of the drivespring 9. However, the derived energy is low due to the low holdingforce.

FIG. 6 shows a longitudinal section of the drive subassembly 1.1 of thedrug delivery device 1 comprising the audible indicator 13 according tothe first embodiment.

The resilient force member 13.1 is in the relaxed state S1, wherein thedrug delivery device 1 is in a state at the end of a medicament deliveryprocess.

For delivering the medicament M through the needle 4 into an injectionsite, e.g. a patient's skin, the plunger 10 is moved distally from aproximal position to a distal position due to an activation of the drivespring 9. The activation of the drive spring 9 may be initiated bypressing a button or by depressing the needle shroud 7 as it is pushedagainst the injection site.

In FIG. 6, the plunger 10 has reached the distal position, wherein theflexible arm 15.2 is no longer engaged with the plunger 10. When aproximal end of the plunger 10 passes the distal end of the flexible arm15.2, the flexible arm 15.2 is allowed to relax and can thus moveradially inwards driven by the distally pointing end 13.1.1 of theresilient force member 13.1. As the distally pointing end 13.1.1 of theresilient force member 13.1 moves, the resilient force member 13.1 cantransition from a generally biased state S2 into a generally relaxedstate S1 releasing stored energy to generate an audible signal, such asa click noise, due to a transition from the second conformation to thefirst conformation. Due to the large amount of stored energy, theaudible signal can be generated with a high intensity, e. g. up to 100decibels. Signals of lesser intensity can also be generated. Theproximally pointing end 13.1.2 of the resilient force member 13.1 canalso swing radially inwards, thereby hitting the flexible arm 15.2 orthe case 2 or another component of the drug delivery device 1. Thisimpact may also contribute to the generation of the audible signal.

The user or patient recognizing the audible signal knows that themedicament delivery process is finished and that the full dose wasdispensed.

The drug delivery device 1 further comprises a carrier 16 to allow anaccurate support of the syringe 3 during and after an assemblingprocess. The carrier 16 is adapted to assemble, position and to hold thesyringe 3 within the case 2.

FIGS. 7 to 11 respectively show an audible indicator 113 according to asecond embodiment.

FIG. 7 shows a schematic perspective partial section of an exemplaryembodiment of a drug delivery device 101 comprising the audibleindicator 113 according to the second embodiment.

The drug delivery device 101 is configured as an autoinjector nearlysimilar to the description of FIG. 1.

Except for the rear case 102.2 and the audible indicator 113, allcomponents of the drug delivery device 101 have the same configurationas described above in the FIGS. 1 to 6. The audible indicator 113according to the second embodiment will be described in more detail inFIG. 8. The rear case 102.2 will be described in more detail in FIG. 9.

FIG. 8 is a perspective view of the audible indicator 113 according tothe second embodiment.

The audible indicator 113 comprises a resilient force member 113.1 thatmay be configured as a bistable leaf spring comprising a resilientmaterial, e. g. spring steel or spring plastic. Thus, the resilientforce member 113.1 is capable of residing in two states. That is, theresilient force member 113.1 may assume two different stableconformations with limited or no application of an external force. Forexample, these two states can include a first or relaxed state S1 (orpre-assembly state, or triggered state), in which the resilient forcemember 113.1 has a first conformation. In a second or biased state S2(or primed state), the resilient force member 113.1 can have a secondconformation. The resilient force member 113.1 may comprise asubstantially rectangular shape and a longitudinal axis L100 running inparallel to the longest side of the outer circumference of the resilientforce member 113.1.

The resilient force member 113.1 further comprises a longitudinal bend113.2 that is arranged in the centre of the resilient force member 113.1running in parallel to the longitudinal axis L100. The longitudinal bend113.2 can divide the audible indicator 113 into two wing-shaped sectionsangled to each other with an angle less than 180 degrees. In theillustrated perspective of FIG. 8, the wing-shaped sections are angledupwards.

The resilient force member 113.1 comprises a proximal spring section113.3 and a distal spring section 113.4 divided by a cross bend 113.5running in parallel to an axis A100 that may be perpendicular to thelongitudinal axis L100.

According to the present embodiment, the proximal spring section 113.3is longer than the distal spring section 113.4 with respect to thelongitudinal axis L100. In alternative embodiments, the proximal springsection 113.3 may be shorter than the distal spring section 113.4 orhave the same length.

The resilient force member 113.1 is coupled to the rear case 102.2 asshown in the following FIG. 9.

FIG. 9 shows a schematic perspective view of an exemplary embodiment ofthe drive sub assembly 101.1 of the drug delivery device 101.

The rear case 102.2 comprises two support arms 115.1 similar to the onesdescribed in FIG. 4. According to the present embodiment, the supportarms 115.1 are configured with different lengths with respect to thelongitudinal axis L100 in an assembled state of the audible indicator113. In particular, the support arm 115.1 carrying the resilient forcemember 113.1 is shorter than the other support arm 115.1 in order tocreate space for arranging the resilient force member 113.1. Theresilient force member 113.1 may be coupled to the support arm 115.1 bya positive fit connection. For example, the proximal spring section113.3 is received within a guiding recess arranged on an inner side ofthe support arm 115.1 and fixed, e.g. by a snap connection, by welding,gluing or by a frictional fit, wherein a remaining section of theproximal spring section 113.3 and the distal spring section 113.4project distally from the support arm 115.1.

The illustrated resilient force member 113.1 is in the biased state S2,wherein the distal spring section 113.4 is directed towards the outercircumference of a plunger 110 with respect to the proximal springsection 113.3.

Due to the decreased diameter of a distal plunger section 110.2 (similarto the plunger 10 shown in FIG. 1), the distal spring section 113.4 isradially spaced from the outer circumference of the distal plungersection 110.2. Furthermore, the distal spring section 113.4 is notsupported by any component of the drug delivery device 101 as can beseen in FIG. 10.

FIG. 10 shows a schematic longitudinal section of a proximal part of thedrug delivery device 101 comprising the audible indicator 113 accordingto the second embodiment in the biased state S2, wherein the resilientforce member 113.1 stores a certain amount of energy. The plunger 110 isin the proximal position. Thus, the drug delivery device 101 is ready tostart a medicament delivery process.

For delivering a medicament M through a needle 104 into an injectionsite, the plunger 110 has to be moved distally from the proximalposition to the distal position as illustrated in FIG. 11 due to theactivation of a drive spring 109 as described above.

FIG. 11 shows a schematic longitudinal section of the proximal part ofthe drug delivery device 101 with the plunger 110 in the distal positionand the audible indicator 113 in the relaxed state S1.

At the end of medicament delivery, the proximal plunger section 110.1abuts the distal spring section 113.4. The abutting generates a forceinfluence on the resilient force member 113.1, which causes the distalspring section 113.5 to deflect radially outwards. As a result, theresilient force member 113.1, in particular the distal spring section113.4 releases the energy and thus can transition from a generallybiased state S2 into a generally relaxed state S1, thereby generating arecognizable audible signal.

FIGS. 12 to 16 respectively show an audible indicator 213 according to athird embodiment.

FIG. 12 shows a schematic perspective partial section of an exemplaryembodiment of a drug delivery device 201 comprising the audibleindicator 213 according to the third embodiment.

The drug delivery device 201 is configured as an autoinjector similar tothe one described in FIG. 1.

Except for the rear case 202.2 and the audible indicator 213, allcomponents of the drug delivery device 201 may have the sameconfiguration as described above in the FIGS. 1 to 6. The audibleindicator 213 according to the third embodiment will be described inmore detail in FIG. 13. The rear case 202.2 will be described in moredetail in FIG. 14.

FIG. 13 is a perspective view of the audible indicator 213 according tothe second embodiment.

The audible indicator 213 comprises a resilient force member 213.1 thatis configured as a bistable leaf spring comprising a resilient material,e. g. spring steel or spring plastic. Thus, the resilient force member213.1 is capable of residing in two states. That is, the resilient forcemember 213.1 may assume two different stable conformations with limitedor no application of an external force. For example, these two statescan include a first or relaxed state S1 (or pre-assembly state, ortriggered state), in which the resilient force member 213.1 has a firstconformation. In a second or biased state S2 (or primed state), theresilient force member 213.1 can have a second conformation. Theresilient force member 213.1 may comprise a substantially rectangularshape and a longitudinal axis L200 running in parallel to the longestside of the outer circumference of the resilient force member 213.1.

The resilient force member 213.1 further comprises a longitudinal bend213.2 that may be arranged generally in the centre of the resilientforce member 213.1 running in parallel to the longitudinal axis L200.The longitudinal bend 213.2 divides the resilient force member 213.1into two wing-shaped sections angled to each other with an angle lessthan 180 degrees. In the illustrated perspective view of FIG. 13, thewing-shaped sections are angled upwards.

The resilient force member 213.1 is coupled to the rear case 202.2 asshown and described in the following FIG. 14.

FIG. 14 shows a schematic perspective view of an exemplary embodiment ofa drive sub assembly 201.1 of the drug delivery device 201.

The rear case 202.2 comprises two support arms 215.1 nearly similar tothe ones shown in FIG. 4.

According to the present embodiment, the support arms 215.1 have thesame lengths with respect the longitudinal axis L200 in an assembledstate of the audible indicator 213. The support arms 215.1 respectivelycomprise a longitudinal recess 215.1.1, wherein the resilient forcemember 213.1 is arranged within the longitudinal recess 215.1.1 of oneof the support arms 215.1. Thus, the resilient force member 213.1 may beproximally fixed to the support arm 215.1 by a positive connection, e.g.a snap connection, in order to prevent rotation of the resilient forcemember 213.1.

The wing-shaped sections of the resilient force member 213.1 are bentupwards away from a plunger 210.

For assembling the audible indicator 213 into the drug delivery device201, the resilient force member 213.1 is additionally bent in the centreabout the axis A200 until a kink tip 213.3 is generated and theresilient force member 213.1 can transition from a generally relaxedstate S1 into a generally biased state S2 as illustrated in FIG. 15,wherein the kink tip 213.3 points towards the outer circumference of theplunger 210. This bending may be achieved by applying a predeterminedforce onto the centre point of the resilient force member 213.1.Likewise, this bending may be achieved by supporting the proximal end ofthe resilient force member 213.1 close to the kink point and applying apredetermined force, e.g. 20 N to the distal end of the resilient forcemember 213.1. The kink tip 213.3 may be only achieved if thelongitudinal bend 213.2 has a sufficiently small angle and bend radiusand if a sufficiently small bend radius and sufficiently largedeflection are applied when generating the kink tip 213.3.

FIG. 15 shows a schematic longitudinal section of the drive sub assembly201.1 comprising the audible indicator 213 according to the thirdembodiment in the biased state S2, wherein the resilient force member213.1 stores a certain amount of energy. The plunger 10 is in theproximal position and the kink tip 213.3 is supported by the outercircumference of the plunger 210. The drug delivery device 201 is readyto start a medicament delivery process.

For delivering a medicament M into an injection site, the plunger 210has to be moved distally from the proximal position to the distalposition as illustrated in FIG. 16.

At the end of medicament delivery, when the plunger 10 passes the kinktip 213.3 distally, a proximal plunger section 210.1 with an increaseddiameter with respect to a distal plunger section 210.1, the kink tip213.3 generates a force influence on the resilient force member 213.1,which causes the kink tip 213.3 to deflect radially outwards asillustrated in FIG. 16.

FIG. 16 shows a schematic longitudinal section of the drive sub assembly201.1 with the plunger 210 in the distal position and the audibleindicator 213 in the relaxed state S1.

Due to the deflection of the kink tip 213.3, the energy is released fromthe resilient force member 213.1, whereby the resilient force member213.1 is straightened with respect to the longitudinal axis L200. Byreleasing the stored energy, the resilient force member 213.1 cantransition from a generally biased state S2 into a generally relaxedstate S1, thereby generating a recognizable audible signal.

FIGS. 17 to 22 respectively show an audible indicator 313 according to afourth embodiment.

FIG. 17 shows a schematic perspective partial section of an exemplaryembodiment of a drug delivery device 301 comprising the audibleindicator 313 according to a fourth embodiment.

The drug delivery device 301 is configured as an autoinjector similar tothe one described in FIG. 1.

Except for the rear case 302.2 and the audible indicator 313, allcomponents of the drug delivery device 301 have the same configurationas described above in the FIGS. 1 to 6. The audible indicator 313according to the fourth embodiment will be described in more detail inFIG. 18. The rear case 302.2 will be described in more detail in FIG.19.

FIG. 18 is a perspective view of the audible indicator 313 according tothe fourth embodiment.

The audible indicator 313 comprises a resilient force member 313.1 thatis configured as a bistable leaf spring comprising a resilient material,e. g. spring steel or spring plastic. Thus, the resilient force member313.1 is capable of residing in two states. That is, the resilient forcemember 313.1 may assume two different stable conformations with limitedor no application of an external force. For example, these two statescan include a first or relaxed state S1 (or pre-assembly state, ortriggered state), in which the resilient force member 313.1 has a firstconformation. In a second or biased state S2 (or primed state), theresilient force member 313.1 can have a second conformation. Theresilient force member 313.1 may comprise a substantially rectangularshape and a longitudinal axis L300 running in parallel to the longestside of the outer circumference of the resilient force member 313.1.

The resilient force member 313.1 further comprises a longitudinal bend313.2 that can be arranged generally in the centre of the resilientforce member 313.1 running in parallel to the longitudinal axis L300.The longitudinal bend 313.2 can divide the resilient force member 313.1into two wing-shaped sections angled to each other with an angle lessthan 180 degrees.

The resilient force member 313.1 may be further divided into a proximalspring section 313.3, an intermediate spring section 313.4 and a distalspring section 313.5 due to a first cross bend 313.6 and a second crossbend 313.7 respectively running in parallel to an axis A300 that may beperpendicular to the longitudinal axis L300.

Additionally, the distal spring section 313.5 comprises a hook-likeprojection 313.5.1 arranged on a distal end of the distal spring section313.5 and protruding diagonally towards a proximal end of the distalspring section 313.5.

The resilient force member 313.1 is coupled to the rear case 302.2 asillustrated in FIG. 19. FIG. 19 shows a schematic perspective view of adrive sub assembly 301.1 of the drug delivery device 1 comprising therear case 302.2, a plunger 310 and the audible indicator 313 accordingto the fourth embodiment.

The rear case 302.2 comprises two support arms 315.1 nearly similar tothe ones described in FIG. 4.

According to the present embodiment, the support arms 315.1 have thesame length with respect to the longitudinal axis L300 in an assembledstate of the audible indicator 313. Alternatively, the support arm 315.1which is not connected to the resilient force member 313.1 could be anylength. The support arms 315.1 respectively comprise a guiding recess315.1.1, wherein the resilient force member 313.1 is received within theguiding recess 315.1.1 of one of the support arms 315.1. Particularly,the proximal spring section 313.3 is arranged within the guiding recess315.1.1, which may comprise guiding tracks for positive locking of theresilient force member 313.1. The arrangement of the proximal springsection 313.3 within the guiding recess 315.1.1 is supported by twolocking tabs 315.1.2 that decrease a cross section of the guiding recess315.1.1 radially above the proximal spring section 313.3.

The intermediate spring section 313.4 and the distal spring section313.5 projects distally from the support arm 315.1, wherein theintermediate spring section 313.4 is angled with respect to the proximalspring section 313.3 radially outwards as best shown in FIG. 20. Thedistal spring section 313.5 is angled radially inwards with respect tothe intermediate spring section 313.4 and thus bent towards the plunger310 as illustrated in FIG. 20. By bending the distal spring section313.5 radially inwards, the resilient force member 313.1 can transitionfrom the relaxed state S1 into the biased state, thereby storing energy.

FIG. 20 shows a schematic longitudinal section of a proximal part of thedrug delivery device 1 comprising the audible indicator 313 according tothe fourth embodiment in the biased state S2, wherein the drug deliverydevice 301 is in an initial state prior to medicament delivery.

The resilient force member 313.1 is supported by a supporting rib 307.7arranged within an inner circumference of a needle shroud 307. Inparticular, the hook-like projection 313.5.1 abuts against thesupporting rib 307.7. Thus, the engagement between the hook-likeprojection 313.5.1 and the supporting rib 307.7 prevents a prematureactivation of the resilient force member 313.1 during storage andtransportation. Alternatively, there may be arranged more than onesupporting rib 307.7

FIG. 21 shows a schematic longitudinal section of the proximal part ofthe drug delivery device 301 comprising the audible indicator 313according to the fourth embodiment in the biased state S2, wherein thedrug delivery device 301 is in a primed state.

Hereby, the drug delivery device 301 is primed for medicament deliveryand thus ready to use. During priming, the needle shroud 307 was movedproximally into a case 302, thus the supporting rib 307.7 movesproximally behind the hook-like projection 313.5.1, thereby generatingspace for the distal spring section 313.5 to deflect radially outwardsas illustrated in FIG. 22. The plunger 310 is in the proximal position,the drug delivery device 301 is ready to start medicament delivery.

For delivering a medicament M into an injection site, the plunger 310has to be moved distally from the proximal position to the distalposition as illustrated in FIG. 22.

FIG. 22 shows a schematic longitudinal section of the proximal part ofthe drug delivery device 301 with the audible indicator 313 in therelaxed state S1 after medicament delivery.

At the end of medicament delivery, the proximal plunger section 310.1abuts the distal spring section 313.5. The abutting generates a forceinfluence on the resilient force member 313.1, which causes the distalspring section 313.5 to deflect radially outwards.

Due to the deflection of the distal spring section 313.5, the energy isreleased from the resilient force member 313.1. By releasing the storedenergy, the resilient force member 313.1 can transition from a generallybiased state S2 into a generally relaxed state S1, thereby generating arecognizable audible signal.

FIGS. 23 to 30 respectively show an audible indicator 413 according to afifth embodiment.

FIG. 23 is a schematic perspective partial section of an exemplaryembodiment of a drug delivery device 401 comprising the audibleindicator 413 according to the fifth embodiment.

The drug delivery device 401 is configured as an autoinjector similar tothe one described in FIG. 1.

Except for the rear case 402.2 and the audible indicator 413, allcomponents of the drug delivery device 401 substantially have the sameconfiguration as described above in the FIGS. 1 to 6. The audibleindicator 413 according to the fifth embodiment will be described inmore detail in FIG. 24. The rear case 402.2 will be described in moredetail in FIG. 26.

FIG. 24 is a perspective view of the audible indicator 413 according tothe fifth embodiment.

The audible indicator 413 comprises a resilient force member 413.1 thatis configured as a bistable leaf spring comprising a resilient material,e. g. spring steel or spring plastic. Thus, the resilient force member413.1 is capable of residing in two states. That is, the resilient forcemember 413.1 may assume two different stable conformations with limitedor no application of an external force. For example, these two statescan include a first or relaxed state S1 (or pre-assembly state, ortriggered state), in which the resilient force member 413.1 has a firstconformation. In a second or biased state S2 (or primed state), theresilient force member 413.1 can have a second conformation. Theresilient force member 413.1 may comprise a substantially rectangularshape and a longitudinal axis L400 running in parallel to the longestside of the outer circumference of the resilient force member 413.1.

The resilient force member 413.1 further comprises a longitudinal bend413.2 that can be arranged generally in the centre of the resilientforce member 413.1 running in parallel to the longitudinal axis L400.The longitudinal bend 413.2 can divide the resilient force member 413.1into two wing-shaped sections angled to each other with an angle lessthan 180 degrees.

The resilient force member 413.1 can be further divided into a proximalspring section 413.3, an intermediate spring section 413.4 and a distalspring section 413.5 due to a first cross bend 413.6 and a second crossbend 413.7 respectively running in parallel to an axis A400 that can beperpendicular to the longitudinal axis L400.

According to FIG. 24, the resilient force member 413.1 is in the biasedstate S2, wherein the distal spring section 413.5 is bent radiallyinwards with respect to the intermediate spring section 413.4 over thesecond cross bend 413.7.

The resilient force member 413.1 is coupled to the rear case 402.2 asillustrated in FIG. 26.

FIG. 25 shows a schematic perspective view of a collar 418 that isassembled to a drive sub assembly 401.1 as illustrated in FIG. 26.

The collar 418 comprises a collar ramp 418.1 that is arranged on anouter circumference of the collar 418 and configured as a diagonallyramped surface.

FIG. 26 shows a schematic perspective view of the drive sub assembly401.1 of the drug delivery device 401 comprising the rear case 402.2, aplunger 410, the audible indicator 413 according to the fifth embodimentand the collar 418.

The rear case 402.2 comprises two support arms 415.1 similar to the onesdescribed in FIG. 4.

According to the present embodiment, the support arms 415.1 have thesame length with respect to the longitudinal axis L400 in an assembledstate of the audible indicator 413. A fixing element 415.2 is arrangedbetween the support arms 415.1 in order to receive the resilient forcemember 413.1.

The intermediate spring section 413.4 and the distal spring section413.5 project distally from the fixing element 415.2, wherein theintermediate spring section 413.4 is angled with respect to the proximalspring section 413.3 radially inwards. The distal spring section 413.5is angled radially outwards with respect to the intermediate springsection 413.4 and thus bent away from the plunger 410 as illustrated inFIG. 27. By bending the distal spring section 413.5 radially outwards,the resilient force member 413.1 can transition from a generally relaxedstate S1 into a generally biased state S2, thereby storing energy.

The resilient force member 413.1, in particular the bent distal springsection 413.5 is supported by an outer circumference of the collar 418that is coupled distally with a distal plunger section 410.2, e. g. by athreaded connection. Thus, the engagement between the distal springsection 413.5 and the collar 418 prevents a premature activation of theresilient force member 413.1 during storage and transportation.

FIG. 27 shows a schematic longitudinal section of a proximal part of thedrug delivery device 401 comprising the audible indicator 413 accordingto the fifth embodiment in the biased state S2, wherein the drugdelivery device 401 is in an initial state prior to medicament delivery.

The collar 418 is prevented against rotation by a number of locking ribs407.8 as illustrated in FIG. 28.

FIG. 28 shows a schematic longitudinal detail section of the drugdelivery device 401 according to FIG. 27 illustrating the collar 418 andthe number of locking ribs 407.8.

According to the illustrated embodiment, a needle shroud 407 is arrangedthat comprises two locking ribs 407.8 arranged on an inner circumferenceof the needle shroud 407. Alternatively, there may be arranged only oneor more than two locking ribs 407.8.

The locking ribs 407.8 extends in parallel to a longitudinal extensionof the drug delivery device 1 and projects radially inwards, whereby thecollar ramp 418.1 projects between the locking ribs 407.8 thuspreventing a rotational movement of the collar 418 with respect to theneedle shroud 407 during storage and transportation.

During priming of the drug delivery device 401, a force is required tomove the needle shroud 407 proximally with respect to the rear case402.2. As a result, the locking ribs 407.8 move along the collar ramp418.1. This movement causes a rotation of the collar 418 with respect tothe plunger 410. Due to the threaded connection, the collar 418 is moveddistally with respect to the resilient force member 413.1 and the bentdistal spring section 413.5 is unsupported as illustrated in FIG. 29.

FIG. 29 shows a schematic longitudinal section of the proximal part ofthe drug delivery device 1 comprising the audible indicator 413according to the fifth embodiment in the biased state S2, wherein thedrug delivery device 401 is in the primed state and the distal springsection 413.5 is unsupported.

Thus, the drug delivery device 401 is ready to start medicamentdelivery.

For delivering a medicament M through a needle 404 into an injectionsite, the plunger 410 has to be moved distally from the proximalposition to the distal position as illustrated in FIG. 30 due to theactivation of a drive spring 409 as described above.

FIG. 30 shows a schematic longitudinal section of the proximal part ofthe drug delivery device 401 with the audible indicator 413 in therelaxed state S1 after medicament delivery.

At the end of medicament delivery, a proximal plunger section 410.1 withan increased diameter with respect to the distal plunger section 410.2abuts the distal spring section 413.5. The abutting generates a forceinfluence on the resilient force member 413.1, which causes the distalspring section 413.5 to deflect radially inwards.

Due to the deflection of the distal spring section 413.5, the energy isreleased from the resilient force member 413.1. By releasing the storedenergy, the resilient force member 413.1 can transition from a generallybiased state S2 into a generally relaxed state S1, thereby generating arecognizable audible signal.

FIGS. 31 to 35 respectively show an audible indicator 513 according to asixth embodiment.

FIG. 31 shows a schematic perspective partial section of an exemplaryembodiment of a drug delivery device 501 comprising an audible indicator513 according to the sixth embodiment.

The drug delivery device 501 is configured as an autoinjector similar tothe one described in FIG. 1.

Except for the rear case 502.2 and the audible indicator 513, allcomponents of the drug delivery device 1 substantially have the sameconfiguration as described above in FIGS. 1 to 6. The audible indicator513 according to the fifth embodiment will be described in more detailin FIG. 32. The rear case 502.2 will be described in more detail in FIG.33.

FIG. 32 is a perspective view of the audible indicator 513 according tothe sixth embodiment.

The audible indicator 513 comprises a resilient force member 513.1 thatis configured as a bistable leaf spring comprising a resilient material,e. g. spring steel or spring plastic. Thus, the resilient force member513.1 is capable of residing in two states. That is, the resilient forcemember 513.1 may assume two different stable conformations with limitedor no application of an external force. For example, these two statescan include a first or relaxed state S1 (or pre-assembly state, ortriggered state), in which the resilient force member 513.1 has a firstconformation. In a second or biased state S2 (or primed state), theresilient force member 513.1 can have a second conformation. Theresilient force member 513.1 may comprise a substantially rectangularshape and a longitudinal axis L500 running in parallel to the longestside of the outer circumference of the resilient force member 513.1.

The resilient force member 513.1 further comprises a longitudinal bend513.2 that can be arranged generally in the centre of the resilientforce member 513.1 running in parallel to the longitudinal axis L500.The longitudinal bend 513.2 divides the resilient force member 513.1into two wing-shaped sections angled to each other with an angle lessthan 180 degrees.

The resilient force member 513.1 can be further divided into a proximalspring section 513.3 and a distal spring section 513.4 due to a crossbend 513.5 that extends in parallel to an axis A500 that may beperpendicular to the longitudinal axis L500.

According to FIG. 32, the resilient force member 513.1 is in the biasedstate S2, wherein the distal spring section 513.5 is bent about acertain angle over the cross bend 513.5 with respect to the proximalspring section 513.3.

With respect to the longitudinal axis L500 the resilient force member513.1 of the present embodiment is smaller than the resilient forcemember 513.1 of the audible indicator 413 of the fifth embodiment.

The resilient force member 513.1 is coupled to the rear case 502.2 asillustrated in FIG. 33.

FIG. 33 shows a schematic perspective view of a drive sub assembly 501.1of the drug delivery device 501 comprising the rear case 502.2, aplunger 510, and the audible indicator 513 according to the sixthembodiment.

The rear case 502.2 comprises two support arms 515.1 similar to the onesdescribed in FIG. 4.

According to the present embodiment, the support arms 515.1 have thesame length with respect to the longitudinal axis L500 in an assembledstate of the audible indicator 513.

The resilient force member 513.1 is coupled to the plunger 510, whereinthe distal spring section 513.4 is fixed to a proximal plunger section510.1 by a force fit, form fit and/or adhesive bond in order to preventa rotational movement of the resilient force member 513.1 with respectto the plunger 510. The proximal spring section 513.3 defines a free endof the resilient force member 513.1 that protrudes beyond the edge ofthe proximal plunger section 510.1 as illustrated in FIG. 34.

The proximal spring section 513.3 is angled radially inwards withrespect to the distal spring section 513.4; hence the resilient forcemember 513.1 is in the biased state S2, thereby storing energy.

The resilient force member 513.1, in particular the proximal springsection 513.3, is supported by the rear case 502.2 as illustrated anddescribed in more detail in FIG. 34.

FIG. 34 shows a schematic longitudinal section of a proximal part of thedrug delivery device 501 comprising the audible indicator 513 accordingto the sixth embodiment.

The drug delivery device 501 is in a primed state prior to use, whereinthe plunger 510 is in a proximal position.

The proximal spring section 513.3 is supported by a supportingprotrusion 502.2.1 arranged on an inner side of a proximal end of therear case 502.2 projecting distally towards the plunger 510. Thesupporting protrusion 502.2.1 may be configured as a protruding sectionor as a circulated ring-shaped protrusion.

The proximal spring section 513.3 is arranged behind the supportingprotrusion 502.2.1 with respect to a radial inward direction and is thusprevented against deflecting radially outwards during storage,transportation and priming of the drug delivery device 501. Furthermore,the cross bend 513.5 defines a kink enabling the bistability of theresilient force member 513.1.

For delivering a medicament M through a needle 504 into an injectionsite, the plunger 510 has to be moved distally from the proximalposition to the distal position as illustrated in FIG. 35 due to theactivation of a drive spring 509 as described above. Because the distalspring section 513.4 is fixed to the proximal plunger section 510.1, theresilient force member 513.1 follows the axial movement of the plunger510. Consequently, the resilient force member 513.1 moves distally withrespect to the rear case 502.2, away from the supporting protrusion502.2.1, wherein the proximal spring section 513.3 becomes unsupported.

At the end of medicament delivery, an activating rib 507.9 arranged onan inner circumference of a needle shroud 507 abuts the resilient forcemember 513.1 at the cross bend 513.5. This abutting generates a forceinfluence on the resilient force member 513.1, which stimulates theproximal spring section 413.5 to deflect radially outwards.

Due to the deflection of the proximal spring section 513.5, the energyis released from the resilient force member 513.1. By releasing thestored energy, the resilient force member 513.1 can transition from agenerally biased state S2 into a generally relaxed state S1 asillustrated in FIG. 35, thereby generating a recognizable audiblesignal.

FIG. 35 shows a schematic longitudinal section of the proximal part ofthe drug delivery device 501, wherein the audible indicator 513 is inthe biased state S2, but on the point of activation as it is starting tocontact the needle shroud 507.

FIGS. 36 to 40 respectively show an audible indicator 613 according to aseventh embodiment.

FIG. 36 shows a schematic perspective partial section of an exemplaryembodiment of a drug delivery device 601 comprising an audible indicator613 according to a seventh embodiment.

The drug delivery device 601 is configured as an autoinjector similar tothe one described in FIG. 1.

Except for the rear case 602.2 and the audible indicator 613, allcomponents of the drug delivery device 601 substantially have the sameconfiguration as described above in the FIGS. 1 to 6.

The audible indicator 613 according to the seventh embodiment will bedescribed in more detail in FIG. 32. The rear case 602.2 will bedescribed in more detail in FIG. 37.

FIG. 37 is a perspective view of the audible indicator 613 according tothe seventh embodiment.

The audible indicator 613 comprises a resilient force member 613.1 thatis configured as a monostable leaf spring comprising a resilientmaterial, e. g. spring steel or spring plastic. Thus, the resilientforce member 613.1 is capable of residing in two states. That is, theresilient force member 613.1 may assume two different conformations, oneof them stable with limited or no application of an external force andthe other one unstable. For example, these two states can include afirst or relaxed state S1 (or pre-assembly state, or triggered state),in which the resilient force member 613.1 has a first conformation. In asecond or biased state S2 (or primed state), the resilient force member613.1 can have a second conformation. The resilient force member 613.1may comprise a substantially rectangular shape and a longitudinal axisL600 running in parallel to the longest side of the outer circumferenceof the resilient force member 613.1.

The resilient force member 613.1 further comprises a longitudinal bend613.2 that may be arranged generally in the centre of the resilientforce member 613.1 running in parallel to the longitudinal axis L600.The longitudinal bend 613.2 divides the resilient force member 613.1into two wing-shaped sections angled to each other with an angle lessthan 180 degrees.

The resilient force member 613.1 is coupled to the rear case 602.2 asillustrated in FIG. 38.

FIG. 38 shows a schematic perspective view of a drive sub assembly 601.1of the drug delivery device 601 comprising the rear case 602.2, aplunger 610, and the audible indicator 613 according to the seventhembodiment.

The rear case 602.2 comprises two support arms 615.1 similar to the onesdescribed in FIG. 14.

According to the present embodiment, the support arms 615.1 have thesame length with respect to the longitudinal axis L600 in an assembledstate of the audible indicator 613. The support arms 615.1 respectivelycomprise a longitudinal recess 615.1.1, wherein the resilient forcemember 613.1 is arranged within the longitudinal recess 615.1.1 of oneof the support arms 615.1. Thereby, the resilient force member 613.1 isproximally and distally fixed to the support arm 615.1 by a positiveconnection, e. g. a snap connection, in order to prevent a rotation ofthe resilient force member 613.1. Alternatively, the fixing could allowrotation of the ends of the resilient force member 613.1, but preventtranslational movement.

The wing-shaped sections of the resilient force member 613.1 are bentupwards away from the plunger 610.

According to the present embodiment, the audible indicator 613 comprisesonly a monostability in contrast to the bistable resilient force members113.1 to 513.1 of some of the other embodiments. That means, theresilient force member 613.1 needs to be supported for remaining in abiased state S2 as illustrated and described in more detail in FIG. 39.

FIG. 39 shows a schematic longitudinal section of a proximal part of thedrug delivery device 601, wherein the resilient force member 613.1 is inthe biased state S2 and the drug delivery device 601 is in a primedstate prior to use, wherein the plunger 610 is in a proximal position.

The support of the resilient force member 613.1 is achieved by acantilever beam 602.2.1 arranged on a section of the support arm 615.1behind the resilient force member 613.1 with respect to a radial inwarddirection. Thus, the resilient force member 613.1 rests on thecantilever beam 602.2.1, whereby the resilient force member 613.1 isadditionally bent in the center about an axis A600 that runs generallyperpendicular to the longitudinal axis L600, thereby generating a kinktip 613.3.

The cantilever beam 602.2.1 is biased radially outwards by an outercircumference of the plunger 610. According to the present embodiment,the rear case 602.2 comprises two cantilever beams 602.2.1.Alternatively, the rear case 602.2 may comprise only one or more thantwo cantilever beams 602.2.1. In embodiments with more than oneresilient force member 613.1, each cantilever beam 602.2.1 may bearranged to support one respective resilient force member 613.1.

For delivering a medicament M into an injection site, the plunger 610has to be moved distally from the proximal position to the distalposition as illustrated in FIG. 40. During medicament delivery, theresilient force member 613.1 is supported by the cantilever beam602.2.1. During movement of the plunger 610, a friction is induced onthe cantilever beam 602.2.1.

At the end of medicament delivery, when a proximal end of the plunger610 passes the cantilever beam 602.2.1 distally, the cantilever beam602.2.1 is free to relax radially inwards. Consequently, the resilientforce element 613.1 relaxes, thereby generating a recognizable audiblesignal.

FIG. 40 shows a schematic longitudinal section of the proximal part ofthe drug delivery device 601, wherein the resilient force element 613 isin the relaxed state S1 after medicament delivery.

The skilled person readily understands that application of the audibleindicator 13 is not limited to auto-injectors 1. Instead, the audibleindicator 13 may likewise be applied in a manually operated drugdelivery device 1 for indicating that the plunger 10 has been completelymoved into the distal position.

In an exemplary embodiment, the bistable or monostable resilient forcemember 13.1, 113.1, 213.1, 313.1, 413.1, 513.1, 613.1 may consist ofstainless steel, e.g. stainless steel 301 full hard. In an exemplaryembodiment the resilient force member 13.1, 113.1, 213.1, 313.1, 413.1,513.1, 613.1 may have a substantially rectangular form, in particularwith a length of 70 mm. A nominal width flat of the resilient forcemember 13.1, 113.1, 213.1, 313.1, 413.1, 513.1, 613.1 may beapproximately 8 mm. The longitudinal bend 13.2, 113.2, 213.2, 313.2,413.2, 513.2, 613.2 may be positioned to bisect the width of theresilient force member 13.1, 113.1, 213.1, 313.1, 413.1, 513.1, 613.1. Athickness of the resilient force member 13.1, 113.1, 213.1, 313.1,413.1, 513.1, 613.1 may be 0.1 mm. In the first conformation, theresilient force member 13.1, 113.1, 213.1, 313.1, 413.1, 513.1, 613.1may be bent about the longitudinal bend 13.2, 113.2, 213.2, 313.2,413.2, 513.2, 613.2 such that the two-wing-shaped sections are at anangle of between 130 and 160 or between 130 degrees and 150 degrees. Forexample, the angle can be between 130 degrees and 140 degrees or between140 degrees and 155 degrees or between 132 degrees and 142 degrees orbetween 134 degrees and 140 degrees or between 136 degrees and 138degrees. In an exemplary embodiment the angle is approximately orexactly 136 degrees or 137 degrees or 138 degrees or 148 degrees or 152degrees relative to each other.

In other exemplary embodiments, the resilient force member 13.1, 113.1,213.1, 313.1, 413.1, 513.1, 613.1 may have a different length, e.g.approximately 30 mm or 43 mm.

In order to kink the resilient force member 13.1, 113.1, 213.1, 313.1,413.1, 513.1, 613.1 to move it from the first conformation to the secondconformation a force in the range from 3 N to 14 N may be applied to afree end of the resilient force member 13.1, 113.1, 213.1, 313.1, 413.1,513.1, 613.1 or to a point near the free end, e.g. approximately 13 mmfrom the free end. Application of this force may result in an extensionof 2 mm to 3.5 mm of the free end from its position in the firstconformation.

A force required to activate the resilient force member 13.1, 113.1,213.1, 313.1, 413.1, 513.1, 613.1 to move it from its secondconformation to its first conformation may be in a range from 0.2 N to0.4 N applied to the free end of the resilient force member 13.1, 113.1,213.1, 313.1, 413.1, 513.1, 613.1 or to a point near the free end, e.g.approximately 1 mm to 2 mm from the free end.

A particularly clear click noise and reduced kinking and activationforces may be achieved by kinking the resilient force member 13.1,113.1, 213.1, 313.1, 413.1, 513.1, 613.1, activating it and then kinkingit again before inserting it into the drug delivery device 1, 101, 201,301, 401, 501, 601.

When activated, the resilient force member 13.1, 113.1, 213.1, 313.1,413.1, 513.1, 613.1 may produce an audible signal with a volume of atleast 100 dB, e.g. measured at a distance of approximately 0.5 m. Asopposed to a resilient force member 13.1, 113.1, 213.1, 313.1, 413.1,513.1, 613.1 with a bend angle of e.g. 152 degrees, the volume producedby a resilient force member 13.1, 113.1, 213.1, 313.1, 413.1, 513.1,613.1 having a bend angle of e.g. 136 degrees can be increased byapproximately 6 dB, which corresponds to a factor 2 increase inamplitude.

When inserted in a drug delivery device 1, 101, 201, 301, 401, 501, 601,the resilient force member 13.1, 113.1, 213.1, 313.1, 413.1, 513.1,613.1 may produce an audible signal with a volume of at least 100 dB(A),e.g. measured at a distance of approximately 150 mm. In a test setup,the drug delivery device 1, 101, 201, 301, 401, 501, 601 was placed in asound-absorbing environment on a table with the needle shroud 7, 307,407, 507 ahead. An elastomeric layer was located between the needleshroud 7, 307, 407, 507 and the table to acoustically decouple the drugdelivery device 1, 101, 201, 301, 401, 501, 601 from the table. Twomicrophones (e.g. ROGA MI-17 (IEPE)) were placed laterally from the drugdelivery device 1, 101, 201, 301, 401, 501, 601 opposite each other at adistance of 150 mm, respectively and 170 mm above the table. A firsttest was performed with a user holding and operating the drug deliverydevice 1, 101, 201, 301, 401, 501, 601 with the right hand closed aroundthe drug delivery device 1, 101, 201, 301, 401, 501, 601, wherein thefingers of the hand covered one side of the drug delivery device 1, 101,201, 301, 401, 501, 601 directed towards one of the microphones andwherein the opposite side pointing towards the other microphone wascovered by the palm of the hand. The volume of the audible signal on thefinger side microphone was at least 100 dB(A) while the volume on thepalm side microphone was lower than 100 dB(A). Another test wasperformed with a user holding and operating the drug delivery device 1,101, 201, 301, 401, 501, 601 only with the fingertips of the right hand,wherein the palm of the hand was located between the drug deliverydevice 1, 101, 201, 301, 401, 501, 601 and one of the microphones;however, the drug delivery device 1, 101, 201, 301, 401, 501, 601 wasnot touched by the palm. The volume of the audible signal acquired byboth microphones was at least 100 dB(A), wherein the volume detected bythe palm side microphone was slightly lower than the volume detected bythe other microphone.

The terms “drug” or “medicament” are used herein to describe one or morepharmaceutically active compounds. As described below, a drug ormedicament can include at least one small or large molecule, orcombinations thereof, in various types of formulations, for thetreatment of one or more diseases. Exemplary pharmaceutically activecompounds may include small molecules; polypeptides, peptides andproteins (e.g., hormones, growth factors, antibodies, antibodyfragments, and enzymes); carbohydrates and polysaccharides; and nucleicacids, double or single stranded DNA (including naked and cDNA), RNA,antisense nucleic acids such as antisense DNA and RNA, small interferingRNA (siRNA), ribozymes, genes, and oligonucleotides. Nucleic acids maybe incorporated into molecular delivery systems such as vectors,plasmids, or liposomes. Mixtures of one or more of these drugs are alsocontemplated.

The term “drug delivery device” shall encompass any type of device orsystem configured to dispense a drug into a human or animal body.Without limitation, a drug delivery device may be an injection device(e.g., syringe, pen injector, auto injector, large-volume device, pump,perfusion system, or other device configured for intraocular,subcutaneous, intramuscular, or intravascular delivery), skin patch(e.g., osmotic, chemical, micro-needle), inhaler (e.g., nasal orpulmonary), implantable (e.g., coated stent, capsule), or feedingsystems for the gastro-intestinal tract. The presently described drugsmay be particularly useful with injection devices that include a needle,e.g., a small gauge needle.

The drug or medicament may be contained in a primary package or “drugcontainer” adapted for use with a drug delivery device. The drugcontainer may be, e.g., a cartridge, syringe, reservoir, or other vesselconfigured to provide a suitable chamber for storage (e.g., short- orlong-term storage) of one or more pharmaceutically active compounds. Forexample, in some instances, the chamber may be designed to store a drugfor at least one day (e.g., 1 to at least 30 days). In some instances,the chamber may be designed to store a drug for about 1 month to about 2years. Storage may occur at room temperature (e.g., about 20° C.), orrefrigerated temperatures (e.g., from about −4° C. to about 4° C.). Insome instances, the drug container may be or may include a dual-chambercartridge configured to store two or more components of a drugformulation (e.g., a drug and a diluent, or two different types ofdrugs) separately, one in each chamber. In such instances, the twochambers of the dual-chamber cartridge may be configured to allow mixingbetween the two or more components of the drug or medicament prior toand/or during dispensing into the human or animal body. For example, thetwo chambers may be configured such that they are in fluid communicationwith each other (e.g., by way of a conduit between the two chambers) andallow mixing of the two components when desired by a user prior todispensing. Alternatively or in addition, the two chambers may beconfigured to allow mixing as the components are being dispensed intothe human or animal body.

The drug delivery devices and drugs described herein can be used for thetreatment and/or prophylaxis of many different types of disorders.Exemplary disorders include, e.g., diabetes mellitus or complicationsassociated with diabetes mellitus such as diabetic retinopathy,thromboembolism disorders such as deep vein or pulmonarythromboembolism. Further exemplary disorders are acute coronary syndrome(ACS), angina, myocardial infarction, cancer, macular degeneration,inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis.

Exemplary drugs for the treatment and/or prophylaxis of diabetesmellitus or complications associated with diabetes mellitus include aninsulin, e.g., human insulin, or a human insulin analogue or derivative,a glucagon-like peptide (GLP-1), GLP-1 analogues or GLP-1 receptoragonists, or an analogue or derivative thereof, a dipeptidyl peptidase-4(DPP4) inhibitor, or a pharmaceutically acceptable salt or solvatethereof, or any mixture thereof. As used herein, the term “derivative”refers to any substance which is sufficiently structurally similar tothe original substance so as to have substantially similar functionalityor activity (e.g., therapeutic effectiveness).

Exemplary insulin analogues are Gly(A21), Arg(B31), Arg(B32) humaninsulin (insulin glargine); Lys(B3), Glu(B29) human insulin; Lys(B28),Pro(B29) human insulin; Asp(B28) human insulin; human insulin, whereinproline in position B28 is replaced by Asp, Lys, Leu, Val or Ala andwherein in position B29 Lys may be replaced by Pro; Ala(B26) humaninsulin; Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30)human insulin.

Exemplary insulin derivatives are, for example, B29-N-myristoyl-des(B30)human insulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoylhuman insulin; B29-N-palmitoyl human insulin; B28-N-myristoylLysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin;B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30human insulin; B29-N—(N-palmitoyl-gamma-glutamyl)-des(B30) humaninsulin; B29-N—(N-lithocholyl-gamma-glutamyl)-des(B30) human insulin;B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin andB29-N-(ω-carboxyheptadecanoyl) human insulin. Exemplary GLP-1, GLP-1analogues and GLP-1 receptor agonists are, for example:Lixisenatide/AVE0010/ZP10/Lyxumia,Exenatide/Exendin-4/Byetta/Bydureon/ITCA 650/AC-2993 (a 39 amino acidpeptide which is produced by the salivary glands of the Gila monster),Liraglutide/Victoza, Semaglutide, Taspoglutide, Syncria/Albiglutide,Dulaglutide, rExendin-4, CJC-1134-PC, PB-1023, TTP-054,Langlenatide/HM-11260C, CM-3, GLP-1 Eligen, ORMD-0901, NN-9924, NN-9926,NN-9927, Nodexen, Viador-GLP-1, CVX-096, ZYOG-1, ZYD-1, GSK-2374697,DA-3091, MAR-701, MAR709, ZP-2929, ZP-3022, TT-401, BHM-034. MOD-6030,CAM-2036, DA-15864, ARI-2651, ARI-2255, Exenatide-XTEN andGlucagon-Xten.

An exemplary oligonucleotide is, for example: mipomersen/Kynamro, acholesterol-reducing antisense therapeutic for the treatment of familialhypercholesterolemia.

Exemplary DPP4 inhibitors are Vildagliptin, Sitagliptin, Denagliptin,Saxagliptin, Berberine. Exemplary hormones include hypophysis hormonesor hypothalamus hormones or regulatory active peptides and theirantagonists, such as Gonadotropine (Follitropin, Lutropin,Choriongonadotropin, Menotropin), Somatropine (Somatropin),Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin,Buserelin, Nafarelin, and Goserelin.

Exemplary polysaccharides include a glucosaminoglycane, a hyaluronicacid, a heparin, a low molecular weight heparin or an ultra-lowmolecular weight heparin or a derivative thereof, or a sulphatedpolysaccharide, e.g. a poly-sulphated form of the above-mentionedpolysaccharides, and/or a pharmaceutically acceptable salt thereof. Anexample of a pharmaceutically acceptable salt of a poly-sulphated lowmolecular weight heparin is enoxaparin sodium. An example of ahyaluronic acid derivative is Hylan G-F 20/Synvisc, a sodiumhyaluronate.

The term “antibody”, as used herein, refers to an immunoglobulinmolecule or an antigen-binding portion thereof. Examples ofantigen-binding portions of immunoglobulin molecules include F(ab) andF(ab′)2 fragments, which retain the ability to bind antigen. Theantibody can be polyclonal, monoclonal, recombinant, chimeric,de-immunized or humanized, fully human, non-human, (e.g., murine), orsingle chain antibody. In some embodiments, the antibody has effectorfunction and can fix complement. In some embodiments, the antibody hasreduced or no ability to bind an Fc receptor. For example, the antibodycan be an isotype or subtype, an antibody fragment or mutant, which doesnot support binding to an Fc receptor, e.g., it has a mutagenized ordeleted Fc receptor binding region.

The terms “fragment” or “antibody fragment” refer to a polypeptidederived from an antibody polypeptide molecule (e.g., an antibody heavyand/or light chain polypeptide) that does not comprise a full-lengthantibody polypeptide, but that still comprises at least a portion of afull-length antibody polypeptide that is capable of binding to anantigen. Antibody fragments can comprise a cleaved portion of a fulllength antibody polypeptide, although the term is not limited to suchcleaved fragments. Antibody fragments that are useful in the presentdisclosure include, for example, Fab fragments, F(ab′)2 fragments, scFv(single-chain Fv) fragments, linear antibodies, monospecific ormultispecific antibody fragments such as bispecific, trispecific, andmultispecific antibodies (e.g., diabodies, triabodies, tetrabodies),minibodies, chelating recombinant antibodies, tribodies or bibodies,intrabodies, nobodies, small modular immunopharmaceuticals (SMIP),binding-domain immunoglobulin fusion proteins, camelized antibodies, andVHH containing antibodies. Additional examples of antigen-bindingantibody fragments are known in the art.

The terms “Complementarity-determining region” or “CDR” refer to shortpolypeptide sequences within the variable region of both heavy and lightchain polypeptides that are primarily responsible for mediating specificantigen recognition. The term “framework region” refers to amino acidsequences within the variable region of both heavy and light chainpolypeptides that are not CDR sequences, and are primarily responsiblefor maintaining correct positioning of the CDR sequences to permitantigen binding. Although the framework regions themselves typically donot directly participate in antigen binding, as is known in the art,certain residues within the framework regions of certain antibodies candirectly participate in antigen binding or can affect the ability of oneor more amino acids in CDRs to interact with antigen.

Exemplary antibodies are anti PCSK-9 mAb (e.g., Alirocumab), anti IL-6mAb (e.g., Sarilumab), and anti IL-4 mAb (e.g., Dupilumab).

The compounds described herein may be used in pharmaceuticalformulations comprising (a) the compound(s) or pharmaceuticallyacceptable salts thereof, and (b) a pharmaceutically acceptable carrier.The compounds may also be used in pharmaceutical formulations thatinclude one or more other active pharmaceutical ingredients or inpharmaceutical formulations in which the present compound or apharmaceutically acceptable salt thereof is the only active ingredient.Accordingly, the pharmaceutical formulations of the present disclosureencompass any formulation made by admixing a compound described hereinand a pharmaceutically acceptable carrier.

Pharmaceutically acceptable salts of any drug described herein are alsocontemplated for use in drug delivery devices. Pharmaceuticallyacceptable salts are for example acid addition salts and basic salts.Acid addition salts are e.g. HCl or HBr salts. Basic salts are e.g.salts having a cation selected from an alkali or alkaline earth metal,e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), whereinR1 to R4 independently of each other mean: hydrogen, an optionallysubstituted C1-C6-alkyl group, an optionally substituted C2-C6-alkenylgroup, an optionally substituted C6-C10-aryl group, or an optionallysubstituted C6-C10-heteroaryl group. Further examples ofpharmaceutically acceptable salts are known to those of skill in thearts. Pharmaceutically acceptable solvates are for example hydrates oralkanolates such as methanolates or ethanolates.

Those of skill in the art will understand that modifications (additionsand/or removals) of various components of the substances, formulations,apparatuses, methods, systems and embodiments described herein may bemade without departing from the full scope and spirit of the presentdisclosure, which encompass such modifications and any and allequivalents thereof.

LIST OF REFERENCES

-   1, 101, 201, 301, 401, 501, 601 drug delivery device-   1.1, 101.1, 201.1, 301.1, 401.1, 501.1, 601.1 drive sub assembly-   2 case-   2.1 front case-   2.2, 102.1, 202.1, 302.1, 402.1, 502.1, 602.2 rear case-   502.2.1 supporting protrusion-   602.2.1 cantilever beam-   2.15 radial stop-   3 medicament container, syringe-   4, 104, 404, 504 needle-   5 protective needle sheath-   6 stopper-   7, 307, 407, 507 needle shroud-   7.6 apertures-   307.7 supporting rib-   407.8 locking rib-   507.9 activation rib-   8 shroud spring-   9, 109, 409, 509 drive spring-   10, 110, 210, 310, 410, 510, 610 plunger-   10.1, 110.1, 210.1, 310.1, 410.1, 510.1 proximal plunger section-   10.2, 110.2, 210.2, 310.2, 410.1, 510.2 distal plunger section-   11 cap-   11.1 grip features-   11.2 grip element-   11.3 compliant beams-   11.4 rib-   12 plunger release mechanism-   13, 113, 213, 313, 413, 513, 613 audible indicator-   13.1, 113.1, 213.1, 313.1, 413.1, 513.1, 613.1 resilient force    member-   13.1.1 distally pointing end-   13.1.2 proximally pointing end-   13.2, 113.2, 213.2, 313.2, 413.2, 513.2, 613.2 longitudinal bend-   13.3 tabs-   113.3 proximal spring section-   113.4 distal spring section-   113.5 cross bend-   213.3 kink tip-   313.3, 413.4, 513.3 proximal spring section-   313.4, 413.4 intermediate spring section-   313.5, 413.5 distal spring section-   313.5.1 hook-like projection-   313.6, 413.6 first cross bend-   313.7, 413.7 second cross bend-   513.4 distal spring section-   513.5 cross bend-   613.3 kink tip-   14 shroud lock mechanism-   15.1, 115.1, 215.1, 315.1, 415.1, 515.1, 615.1 support arms-   215.1.1 longitudinal recess-   315.1.1 guiding recess-   315.1.2, 415.2.1 locking tabs-   415.2 fixing element-   615.1.1 longitudinal recess-   15.2 flexible arm-   15.2.1 projection-   16 carrier-   418 collar-   418.1 collar ramp-   A, A100, A200, A300, A400, A500, A600 axis-   C force-bending curve-   L, L100, L200, L300, L400, L500, L600 longitudinal axis-   M medicament-   S1 relaxed state-   S2 biased state-   x abscissa-   y ordinate-   x1, y2 coordinates-   x2, y1 coordinates

The invention claimed is:
 1. An audible indicator for use with a drugdelivery device, the audible indicator comprising: a bistable resilientforce member configured to reside in two or more states having two ormore different conformations, wherein, in a relaxed state, the bistableresilient force member is relaxed in a first conformation, wherein, in abiased state, the bistable resilient force member is biased to storeenergy in a second conformation different from the first conformation,wherein the bistable resilient force member releases the stored energyto generate an audible signal when changing from the biased state intothe relaxed state due to a transition from the second conformation tothe first conformation, and wherein the bistable resilient force memberis configured to be changed from the biased state to the relaxed stateby a movement of a plunger of the drug delivery device, the plungerbeing configured to displace a drug from a medicament container of thedrug delivery device.
 2. The audible indicator according to claim 1,wherein the bistable resilient force member is configured to be changedfrom the biased state into the relaxed state by the movement of theplunger towards a distal position at an end of a medicament deliveryprocess.
 3. The audible indicator according to claim 1, wherein a distalend of the bistable resilient force member is radially unsupported inthe biased state.
 4. The audible indicator according to claim 1, whereinthe bistable resilient force member comprises a kink tip, wherein thebistable resilient force member is arranged to change from the biasedstate into the relaxed state when a proximal plunger section abuts thekink tip.
 5. The audible indicator according to claim 1, wherein thebistable resilient force member rests in the biased state by support ofa flexible arm arranged on a rear case, wherein the flexible arm isbiased by an outer circumference of the plunger, wherein the bistableresilient force member is arranged to change from the biased state intothe relaxed state when the flexible arm releases.
 6. The audibleindicator according to claim 1, wherein the bistable resilient forcemember rests in the biased state by support of a cantilever beamarranged on a rear case, wherein the cantilever beam is biased by anouter circumference of the plunger, and wherein the bistable resilientforce member is arranged to change from the biased state into therelaxed state when the cantilever beam releases.
 7. The audibleindicator according to claim 1, wherein the audible indicator is capableof producing an audible signal with a volume of at least 100 dB.
 8. Theaudible indicator according to claim 1, wherein the audible indicator isadapted to indicate completion of medicament delivery, wherein thebistable resilient force member includes a leaf spring comprising atleast one wing-shaped section adapted to store the energy on at leastone outer edge or in a central region of the one or more wing-shapedsections, and wherein the bistable resilient force member is configuredto change from the biased state into the relaxed state, when the one ormore wing-shaped sections pivot about a certain angle until the bistableresilient force member reaches the first conformation.
 9. The audibleindicator according to claim 1, wherein the bistable resilient forcemember includes a leaf spring having a longitudinal axis, wherein thebistable resilient force member is bent by a certain angle about thelongitudinal axis forming two angled wing-shaped sections.
 10. Theaudible indicator according to claim 9, wherein the leaf spring has arectangular shape, a square shape or an oval shape.
 11. The audibleindicator according to claim 1, wherein the bistable resilient forcemember is supported in the biased state in order to prevent thetransition into the relaxed state.
 12. The audible indicator accordingto claim 11, wherein the bistable resilient force member is supportedwhen the drug delivery device is in an initial state and in a primedstate, wherein a proximal spring section of the bistable resilient forcemember is supported by a supporting protrusion arranged on a rear case.13. The audible indicator according to claim 11, wherein the bistableresilient force member changes from the biased state into the relaxedstate when an activating rib of a needle shroud abuts a proximal springsection of the bistable resilient force member, and wherein the proximalspring section is bent about an axis perpendicular to a longitudinalaxis with respect to a distal spring section of the bistable resilientforce member when the bistable resilient force member is in the biasedstate.
 14. The audible indicator according to claim 11, wherein a distalend of the bistable resilient force member is radially supported whenthe drug delivery device is in an initial state, and the distal end ofthe bistable resilient force member is radially unsupported when thedrug delivery device is in a primed state.
 15. The audible indicatoraccording to claim 11, wherein a proximal spring section of the bistableresilient force member is supported by a supporting protrusion arrangedon a rear case.
 16. The audible indicator according to claim 11, whereinthe bistable resilient force member transitions from the biased stateinto the relaxed state when a proximal plunger section abuts a distalspring section of the bistable resilient force member, and wherein thedistal spring section is bent about an axis perpendicular to alongitudinal axis with respect to an intermediate spring section of thebistable resilient force member or with respect to a proximal springsection of the bistable resilient force member when the bistableresilient force member is in the biased state.
 17. The audible indicatoraccording to claim 16, wherein a projection arranged on the distalspring section that is supported by a supporting rib arranged on aneedle shroud.
 18. The audible indicator according to claim 16, whereina collar is coupled to the plunger and adapted to support the distalspring section.
 19. A drug delivery device, comprising an audibleindicator, the audible indicator comprising: a bistable resilient forcemember configured to reside in two or more states having two or moredifferent conformations, wherein in a relaxed state, the bistableresilient force member is relaxed in a first conformation, wherein in abiased state, the bistable resilient force member is biased to storeenergy in a second conformation different from the first conformation,wherein the bistable resilient force member releases the stored energyto generate an audible signal when changing from the biased state intothe relaxed state due to a transition from the second conformation tothe first conformation, and wherein the bistable resilient force memberis configured to be changed from the biased state to the relaxed stateby a movement of a plunger of the drug delivery device, the plungerbeing configured to displace a drug from a medicament container of thedrug delivery device.
 20. An audible indicator for use with a drugdelivery device, the audible indicator comprising: a bistable resilientforce member configured to reside in two or more states having two ormore different conformations, wherein, in a relaxed state, the bistableresilient force member is relaxed in a first conformation, wherein, in abiased state, the bistable resilient force member is biased and deformedto store energy in a second conformation different from the firstconformation, and wherein the bistable resilient force member releasesthe stored energy to generate an audible signal when changing from thebiased state into the relaxed state due to a transition from the secondconformation to the first conformation.